The aging of the central nervous system and the development of incapacitating neurological diseases like Alzheimer's disease (AD) are generally associated with a wide range of histological and pathophysiological changes eventually leading to a compromised cognitive status. Although the diverse triggers of the neurodegenerative processes and their interactions are still the topic of extensive debate, the possible contribution of cerebrovascular deficiencies has been vigorously promoted in recent years. Various forms of cerebrovascular insufficiency such as reduced blood supply to the brain or disrupted microvascular integrity in cortical regions may occupy an initiating or intermediate position in the chain of events ending with cognitive failure. When, for example, vasoconstriction takes over a dominating role in the cerebral vessels, the perfusion rate of the brain can considerably decrease causing directly or through structural vascular damage a drop in cerebral glucose utilization. Consequently, cerebral metabolism can suffer a setback leading to neuronal damage and a concomitant suboptimal cognitive capacity. The present review focuses on the microvascular aspects of neurodegenerative processes in aging and AD with special attention to cerebral blood flow, neural metabolic changes and the abnormalities in microvascular ultrastructure. In this context, a few of the specific triggers leading to the prominent cerebrovascular pathology, as well as the potential neurological outcome of the compromised cerebral microvascular system are also going to be touched upon to a certain extent, without aiming at total comprehensiveness. Finally, a set of animal models are going to be presented that are frequently used to uncover the functional relationship between cerebrovascular factors and the damage to neural networks.

Chronic cerebral hypoperfusion has been associated with cognitive decline in aging and Alzheimer's disease. Moreover, the pattern of cerebral blood flow in mild cognitive impairment has emerged as a predictive marker for the progression into Alzheimer's disease. The reconstruction of a pathological condition in animal models is a suitable approach to the unraveling of causal relationships. For this reason, permanent, bilateral occlusion of the common carotid arteries (2VO) in rats has been established as a procedure to investigate the effects of chronic cerebral hypoperfusion on cognitive dysfunction and neurodegenerative processes. Over the years, the 2VO model has generated a large amount of data, revealing the 2VO-related pattern of cerebral hypoperfusion and metabolic changes, learning and memory disturbances, failure of neuronal signaling, and the neuropathological changes in the hippocampus. In addition, the model has been introduced in research into ischemic white matter injury and ischemic eye disease. The present survey sets out to provide a comprehensive summary of the achievements made with the 2VO model, and a critical evaluation and integration of the various results, and to relate the experimental data to human diseases. The data that have accumulated from use of the 2VO model in the rat permit an understanding of the causative role played by cerebral hypoperfusion in neurodegenerative diseases. Thorough characterization of the model suggests that 2VO in the rat is suitable for the development of potentially neuroprotective strategies in neurodegenerative diseases.

A detailed analysis of the cortical projections of the medial septum-diagonal band (MS/DB) complex was carried out by means of anterograde transport of Phaseolus vulgaris leucoagglutinin (PHA-L). The tracer was injected iontophoretically into cell groups of the medial septum (MS) and the vertical and horizontal limbs of the diagonal band of Broca (VDB and HDB), and sections were processed immunohistochemically for the intra-axonally transported PHA-L. The labeled efferents showed remarkable differences in regional distribution in the cortical mantle dependent on the position of the injection site in the MS/DB complex, revealing a topographic organization of the MS/DB-cortical projection. In brief, the lateral and intermediate aspects of the HDB, also referred to as the magnocellular preoptic area, predominantly project to the olfactory nuclei and the lateral entorhinal cortex. The medial part of the HDB and adjacent caudal (angular) part of the VDB are characterized by widespread, abundant projections to medial mesolimbic, occipital, and lateral entorhinal cortices, olfactory bulb, and dorsal aspects of the subicular and hippocampal areas. Projections from the rostromedial part of the VDB and from the MS are preponderantly aimed at the entire hippocampal and retrohippocampal regions and to a lesser degree at the medial mesolimbic cortex. Furthermore, the MS projections are subject to a clear mediolateral topographic arrangement, such that the lateral MS predominantly projects to the ventral/temporal aspects of the subicular complex and hippocampus and to the medial portion of the entorhinal cortex, whereas more medially located cells in the MS innervate more septal/dorsal parts of the hippocampal and subicular areas and more lateral parts of the entorhinal cortex. PHA-L filled axons have been observed to course through a number of pathways, i.e., the fimbria-fornix system, supracallosal stria, olfactory peduncle, and lateral piriform route (the latter two mainly by the HDB and caudal VDB). Generally, labeled projections were distributed throughout all cortical layers, although clear patterns of lamination were present in several target areas. The richly branching fibers were abundantly provided with both "boutons en passant" and terminal boutons. Both distribution and morphology of the labeled basal forebrain efferents in the prefrontal, cingulate, and occipital cortices closely resemble the distribution and morphology of the cholinergic innervation as revealed by immunohistochemical demonstration of choline acetyltransferase. In contrast, the labeled projections to the olfactory, hippocampal, subicular, and entorhinal areas showed a heterogeneous morphology. Here, the distribution of only the thin varicose projections resembled the distribution of cholinergic fibers.

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic. Here, we have identified a TNF-α-induced proinflammatory agent, lipocalin 2 (Lcn2) via gene array in murine primary cortical neurons. Further investigation showed that Lcn2 protein production and secretion were activated solely upon TNFR1 stimulation when primary murine neurons, astrocytes, and microglia were treated with TNFR1 and TNFR2 agonistic antibodies. Lcn2 was found to be significantly decreased in CSF of human patients with mild cognitive impairment and AD and increased in brain regions associated with AD pathology in human postmortem brain tissue. Mechanistic studies in cultures of primary cortical neurons showed that Lcn2 sensitizes nerve cells to β-amyloid toxicity. Moreover, Lcn2 silences a TNFR2-mediated protective neuronal signaling cascade in neurons, pivotal for TNF-α-mediated neuroprotection. The present study introduces Lcn2 as a molecular actor in neuroinflammation in early clinical stages of AD.